This VA CSR&D Merit Review Award for a Clinical Trial proposal describes a 5-year program to support a prospective, placebo-controlled, randomized clinical trial (RCT) evaluating the effect of phosphodiesterase type-5 (PDE-5) inhibition with tadalafil at 40 mg daily over 12 months on exercise capacity in patients with at least moderate pulmonary hypertension (PH) (mean pulmonary artery pressure [mPAP] > 30 mm Hg, pulmonary vascular resistance [PVR]>3.0 Wood units, pulmonary capillary wedge pressure [PCWP] <18 mm Hg) due to chronic obstructive pulmonary disease (COPD) GOLD stage II or higher, FEV1/FVC <70 and FEV1 <79% of predicted). PDE-5 inhibitors are recommended for World Health Organization (WHO) Group 1 PH but there is no evidence based recommendation supporting the use of these inhibitors in COPD-induced PH (WHO Group 3). In order to ensure maximum patient enrollment and to increase the clinical and demographic diversity of patients included in this study, the proposed research will be conducted at three VA sites: Boston VA Healthcare System, Providence VA Medical Center, and the Greater Los Angeles VA Healthcare System. Within the veteran population, COPD ranks among the most common chronic diseases and inflicts a substantial clinical and economic burden on the VA Healthcare System. Importantly, the vast majority of COPD-associated mortality and morbidity, including hospital admissions, is derived from a relatively select subpopulation of patients. There is emerging evidence to suggest that clinically evident PH is a key determinate of risk in COPD for exacerbations and progression of disease. In the current proposal, we provide novel evidence pertinent to the VA Healthcare System to support this assertion: moderate or severe PH is associated with significantly increased rates of COPD-related hospital readmission as compared to similar veterans with COPD and only mild PH. Moreover, this trend was not influenced by differences in conventional measures of COPD disease severity (i.e., FEV1) and was irrespective of supplemental oxygen status. These observations are in support of previously established clinical observations from others demonstrating that traditional COPD therapies, including supplemental oxygen, are ineffective at modulating sustained improvements to cardiopulmonary hemodynamics in patients with COPD and PH. Under physiological conditions, the enzyme phosphodiesterase type-5 (PDE-5) functions to maintain pulmonary vascular tone by degrading cGMP, which is a key signaling intermediary involved in nitric oxide (NO)-dependent signaling. However, in PH due to lung disease, pulmonary vascular levels of NO are diminished while PDE-5 levels are increased. This raises the possibility that PDE-5 inhibition is a potential strategy by which to increase NO bioavailability and attenuate PH in patients with COPD. The central hypothesis of the current proposal is that pharmacological inhibition of PDE-5 will improve functional capacity in patients with COPD-induced moderate to severe PH as assessed by the 6 minute walk test. Our secondary outcome measures will assess whether this change in functional status are accompanied by an improvement in maximal oxygen uptake during cardio-pulmonary testing and/or changes in pulmonary vascular remodeling assessed by invasive cardiopulmonary hemodynamics. Additional information that will be obtained includes non-invasive assessment by 2-dimensional echocardiography of pulmonary artery systolic pressure and right ventricular function, dyspnea severity, health related quality of life assessed by validated standardized questionnaires, and, the frequency of COPD exacerbations at 12 months. Results from this study are expected to define the potential use of PDE-5 inhibitors in COPD-induced PH. If successful, this treatment option may improve quality of life and outcomes for the large number of veterans afflicted with PH due to COPD.